title: Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients.
abstract: The aim was to investigate the effect of UGT1A9, UGT1A8, UGT2B7 and ABCC2 polymorphism on the pharmacokinetics of mycophenolic acid (MPA) and its metabolites phenolic glucuronide (MPAG) and acyl glucuronide (AcMPAG) in Chinese renal transplant recipients. Single nucleotide polymorphisms (SNP) in UGT1A9-118(dT)(9)/(10), UGT1A9 T-440C/C-331T, UGT1A8*3, UGT2B7 G211T, UGT2B7 C802T, ABCC2 C-24T, and ABCC2 G1249A were detected. A total of 46 recipients were enrolled in the pharmacokinetics study at day 30 after kidney transplantation. Differences in the MPA pharmacokinetic profiles confirmed large inter-patient variation of MPA exposure. A statistical significant increase in the dose-adjusted AUC(6-12) level of MPA was found in patients bearing the -118(dT)(10) allele of the UGT1A9 gene (T(9) = 7.34 +/- 4.11 mg h ml(-1) g(-1); T(9)/T(10) = 11.54 +/- 7.62 mg h ml(-1) g(-1); and T(10) = 11.89 +/-8.76 mg h ml(-1) g(-1), p = 0.041). A similar trend was also observed for the dose-adjusted AUC(0-12) and AUC(6-12) of MPAG. Patients carrying the heterozygous mutant alleles of ABCC2 G1249A exhibited higher AUC(6-12)/D of AcMPAG than those with wild-type genotype (p = 0.016). The other SNPs that were genotyped did not cause any significant variation in MPA and MPAG pharmacokinetic parameters. In conclusion, the enterohepatic recirculation of MPA in the patients seems to be more extensive in UGT1A9-118(dT)(10) allele carriers, and the exposure of AcMPAG is higher in patients carrying ABCC2 G1249A genotype than those with wild-type genotype.
authors.affiliation: Institute of Clinical Pharmacology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: W-X
authors.initials: WX
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Jin
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Mao
authors.forename: W
authors.initials: W
authors.lastname: Cai
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006650:Histocompatibility Testing; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D004791:Enzyme Inhibitors; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C000715591:UGT1A9 protein, human; C113145:mycophenolic acid glucuronide; C491474:UGT2B7 protein, human; C454320:UDP-glucuronosyltransferase, UGT1A8